Lower urinary tract symptoms, or LUTS, represent a cluster of chronic urinary disorders that affect millions of men in the U.S. and abroad each year. LUTS is the clinical manifestation of benign prostatic hyperplasia, a condition of unregulated growth in the prostate gland. The prevalence of LUTS increases with age, and many men experience a worsening of their symptoms over time. Consistent with this pattern, our preliminary data among men ages 65 years or older in the Osteoporotic Fractures in Men (MrOS) cohort indicates that about 20% reported clinically relevant progression of symptoms, defined as a change of at least 4 points in symptom score. Despite the burden that LUTS imposes on men's health, surprisingly little is known about factors that affect progression of these symptoms. One barrier has been the view that LUTS are in inevitable process of aging driven by non-modifiable stimuli such as sex steroid hormones. However, exciting new data primarily from cross-sectional studies suggests that modifiable factors, especially those of metabolic origin, could influence LUTS pathogenesis. Thus, our goal is to further elucidate LUTS etiology in order to expand the options for prevention and improve clinical tools for patient prognosis. The primary objectives of this proposal are to 1) determine the risk factors for progression of LUTS among older men and 2) to use the resulting epidemiologic data to develop clinically useful risk prediction models. To accomplish these objectives, we propose a prospective study using comprehensive data already collected among 5,995 US men ages 65-100 years in the MrOS cohort. LUTS have been assessed three times during 5 years of follow-up with the American Urologic Association Symptom Index (AUA-SI), a validated and widely used 7-item instrument. During follow-up, the primary measure of progression will be defined as an increase in AUA score of 4 points, a clinically accepted indicator of relevant symptom progression. Detailed risk factor assessments with a focus on metabolic and lifestyle factors will be performed. Measures relevant to these assessments include total body and trunk fat distribution (quantified directly from dual energy x-ray absorptiometry[DXA]), fasting serum insulin, glucose, lipids, and vitamin D from accurate assays, and physical activity and diet from validated instruments. We will test hypotheses that risk of progression is significantly increased in relation to factors such as greater adiposity and hyperlipidemia, and is significantly reduced in relation to factors such as greater physical activity or higher fruit and vegetable consumption. Analyses will be further stratified by initial symptom level (none/mild, moderate/severe) in order to determine the applicability of any observed associations to symptom severity. Using results of the prospective analysis, we will apply a novel combination of statistical techniques to predict individual risk of experiencing a LUTS outcome. This study will advance knowledge about the natural history of LUTS progression among older men in relation to metabolic and lifestyle factors. By so doing, we expect to identify a variety of new options for the prevention and treatment of LUTS. PUBLIC HEALTH RELEVANCE: Chronic lower urinary tract symptoms, known as LUTS, affect millions of men in the U.S. each year and cost billions of dollars to diagnose and treat. Defining possible causes of and methods for preventing these symptoms remains an understudied area. Results of the proposed research will help determine the clinically relevant characteristics of older men at greatest risk of developing LUTS and uncover potential ways of preventing these bothersome and costly symptoms.